WO2018104729A1

WO2018104729A1 - Ketamine derivatives

Info

Publication number: WO2018104729A1
Application number: PCT/GB2017/053672
Authority: WO
Inventors: Richard MYERSON; Jonathan Hull; Paul Blaney; Peter RANDS; Alan Armstrong
Original assignee: Small Pharma Ltd
Priority date: 2016-12-05
Filing date: 2017-12-05
Publication date: 2018-06-14
Also published as: WO2018104729A8

Abstract

The present invention provides conformationally stabilized analogues of the ketamine metabolites 6-hydroxyketamine and 6-hydroxynorketamine with applications in the treatment of depression disorders and anxiety disorders. In particular the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof; wherein R¹ is H or C1-C4 alkyl; R2 is H or C1-C4 alkyl; R3 is H or C1-C4 alkyl; R4 is H or Ci- C4 alkyl; R5 is H or C1-C4 alkyl; R5 is H or C1-C4 alkyl; and R6 represents 0, 1, 2, 3, 4 or 5 haloatoms each independently selected from F, CI, Br, I, wherein when R2 is H, preferably at least one of R³, R⁴ and R⁵ is not H.

Description

KETAMINE DERIVATIVES

FIELD OF THE INVENTION

The present invention provides conformationally stabilized analogues of the ketamine metabolites 6-hydroxyketamine and 6-hydroxynorketamine with applications in the treatment of depression disorders and anxiety disorders.

In particular the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof;

I

wherein R¹ is H or Ci-C₄ alkyl; R² is H or Ci-C₄ alkyl; R³ is H or Ci-C₄ alkyl; R⁴ is H or Ci- C alkyl; R⁵ is H or Ci-C alkyl; R⁵ is H or Ci-C alkyl; and R⁶ represents 0, 1, 2, 3, 4 or 5 haloatoms each independently selected from F, CI, Br, I, wherein when R² is H, preferably at least one of R³, R⁴ and R⁵ is not H.

BACKGROUND OF THE INVENTION

Ketamine has long been known to be a potent and extremely rapid antidepressant. Ketamine hydrochloride, sold under the brand name Ketalar, is a medication mainly used for starting and maintaining anaesthesia.

Ketamine has been tested in treatment-resistant major depressive disorder, and in depression patients displaying suicidality. It is given as a single intravenous infusion at doses less than those used in anaesthesia. Preliminary data indicate it rapidly reduces symptoms of depression (within 2 hours) and the effects are sustained for about a week. For example, intravenous infusions of 0.5mg/kg of ketamine hydrochloride administered over a period of 40 mins have been shown to exhibit potent and rapid anti -depressant effects in treatment- resistant depression patients, for example in Murrough et al; Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial; Am J Psychiatry. 1 October 2013; 170(10): 1134-1142.

Since discovery of the rapid-acting antidepressant effects of ketamine, the prevailing theory to explain its activity is that the antidepressant effects are a result of antagonism of the N- methyl-D-aspartate (NMD A) receptor, a type of glutamate receptor. Recently, A study conducted in mice found that ketamine's antidepressant activity is not caused by antagonism of the NMDA receptor, but rather by sustained activation of a different glutamate receptor, the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMP A) receptor, by a specific metabolite, (2R,6R)-hydroxynorketamine (Zanos et al; NMDAR inhibition-independent antidepressant actions of ketamine metabolites; Nature (2016); 533 : 481-486). This discovery represents a significant step forward in the understanding of how ketamine treats depression and anxiety.

DEFINITIONS

Throughout the specification one or more aspect of the invention may be combined with one or more feature to define specific embodiments of the invention.

References herein to a singular of a noun encompass the plural of the noun, and vice-versa, unless the context implies otherwise.

As used herein, the term pharmaceutically acceptable salt is defined as the product of an acid addition reaction in which an amine group of a compound of the invention is protonated by an organic or inorganic acid to form a non-toxic salt, or as the product of a base addition reaction in which an acidic group in a compound of the invention is deprotonated by an organic or inorganic base to form a non-toxic salt. The term pharmaceutically acceptable salt includes solvates thereof. Wherever a compound is referred to by its generic or systematic name, the term is taken to include all pharmaceutically acceptable salts.

As used herein H means a hydrogen atom. Also encompassed in the definition of hydrogen atom are isotopes of hydrogen, in particular deuterium.

As used herein C1-C4 alkyl means a saturated carbon chain having one to four carbon atoms and which may be linear or branched. Examples of alkyl groups include methyl (also referred to herein as Me), ethyl, n-propyl, isopropyl, n-butyl, sec- and tert-butyl (also referred to herein as t-Butyl, t-Bu, or *Bu). Such C1-C4 alkyl groups may in some embodiments be substituted with one or more haloatom, particularly fluoro, for example to form a -CF3 group.

When R⁶ represents 0, 1, 2, 3, 4 or 5 haloatoms each independently selected from F, CI, Br, I, each haloatom may replace any aryl hydrogen, and may be located ortho, meta or para to the C-C bond linking the aryl group to the cyclohexanone.

As used herein, F means fluoride, CI means chloride, Br means bromide, I means iodide.

As used herein, -PO3H2 can also mean -PO3H^", and collectively with the oxygen atom to which it is attached represents a phosphate group. As used herein the term -SO3H can also mean -SO3^" and collectively with the oxygen atom to which it is attached represents a sulphate group. In certain embodiments of the invention, the presence of a phosphate group or a sulphate group in compounds of the present invention facilitates formation of a zwitterion wherein the phosphate deprotonated and thus negatively charged and the amino group is protonated and thus positively charged.

As used herein 'solid' means a material characterised by structural rigidity and resistance to changes in shape and volume.

As used herein 'crystalline' refers to a solid material whose constituents are arranged in a highly ordered microscopic structure, forming a lattice.

As used herein 'solid oral dosage form' means a discrete unit suitable for oral administration such as capsules or tablets each containing a predetermined amount of the active ingredient. Alternative dosage forms include a powder, granules, a solution, a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. The dosage forms of the present invention may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both and may be prepared by mixing the principle active agent(s) with a pharmaceutical carrier, e.g. corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, or dicalcium phosphate, and other pharmaceutical diluents, e.g. water, to form a solid pre-formulation composition containing a homogenous mixture of the active agent(s). When referring to these pre-formulation compositions as homogenous, it is meant that the active agent is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. The product can then be conveniently shaped into the desired presentation.

Suitable unit doses of the compounds according to the present invention are between 0.5mg and lOOOmg, or between lmg and 900mg, or between 2mg and 800mg, or between 3mg and 700mg, or between 4mg and 600mg, or between 5mg and 500mg, or between 6mg and 400mg, or between 7mg and 300mg, or between 8mg and 200mg, or between 9mg and 150mg, or between 10 mg and 100 mg, or between 20mg and 90mg, or between 30mg and 80mg, or between 40mg and 70mg, or between 50mg and 60mg.

Quantities of weight provided herein refer to the free-form equivalent of a compound of the present invention.

Suitable unit doses of the serotonin modulators for use in aspects of the present invention include the unit doses for these compounds as described in the Martindale: The Complete Drug Reference (London, the Pharmaceutical Press, 38^th Edition) and US Pharmacopoeia and National Formulary 2016 Edition.

Suitable unit doses for citalopram include lOmg, 20mg and 40mg.

Suitable unit doses for escitalopram include 5mg, lOmg and 20mg.

Suitable unit doses for fluoxetine include 20mg and 60mg.

Suitable unit doses for fluvoxamine include 50mg and lOOmg.

Suitable unit doses for paroxetine include lOmg, 20mg and 30mg.

Suitable unit doses for sertraline include 50mg and lOOmg.

Suitable unit doses for dapoxetine include 30mg and 60mg.

As used herein, room temperature and pressure means a temperature around 298K and pressure around 1 atmosphere.

As used herein, the term 'patient' preferably refers to a human patient, but may also refer to a domestic mammal. The term does not encompass laboratory mammals.

As used herein, the term 'first-line therapy' is defined as the first course of pharmaceutical treatment administered in response to an episode of a disorder. The term 'episode' refers to a single noteworthy happening in the course of a longer series of events, such as one critical period of several during a prolonged disorder.

As used herein, the term 'depressive disorder' is defined as a category of mental disorders characterized by at least one of: (a) depressed mood, such as feeling sad, empty or tearful, and (b) significantly reduced interest or feeling no pleasure in all or most activities over a two-week period, combined with at least one further symptom selected from: (c) significant weight loss when not dieting, weight gain, or decrease or increase in appetite, (d) insomnia or increased desire to sleep; either restlessness or slowed behaviour that can be observed by others (f) fatigue or loss of energy, (g) feelings of worthlessness, or excessive or

inappropriate guilt, (h) trouble making decisions, or trouble thinking or concentrating, and (i) recurrent thoughts of death or suicide, or a suicide attempt. Depressive disorders include: major depression, persistent depressive disorder, bipolar disorder, psychotic depression, postpartum depression, suicidality, premenstrual dysphoric disorder (PMDD) and atypical depression.

Major depressive disorder (MDD), also referred to as clinical depression, is defined as the presence of five or more of the following symptoms over a period of two-weeks or more (also referred to herein as a 'major depressive episode'), most of the day, nearly every day.

depressed mood, such as feeling sad, empty or tearful (in children and teens, depressed mood can appear as constant irritability);

significantly reduced interest or feeling no pleasure in all or most activities;

significant weight loss when not dieting, weight gain, or decrease or increase in appetite (in children, failure to gain weight as expected);

insomnia or increased desire to sleep;

either restlessness or slowed behaviour that can be observed by others;

fatigue or loss of energy;

• feelings of worthlessness, or excessive or inappropriate guilt;

• trouble making decisions, or trouble thinking or concentrating;

• recurrent thoughts of death or suicide, or a suicide attempt;

At least one of the symptoms must be either a depressed mood or a loss of interest or pleasure.

Persistent depressive disorder, also known as dysthymia, is defined as a patient exhibiting the following two features:

A. has depressed mood for most the time almost every day for at least two years. Children and adolescents may have irritable mood, and the time frame is at least one year.

B. While depressed, a person experiences at least two of the following symptoms:

Either overeating or lack of appetite.

Sleeping too much or having difficulty sleeping.

Fatigue, lack of energy.

Poor self-esteem.

Difficulty with concentration or decision making

Feeling hopeless. Bipolar disorder, also known as manic-depressive illness, is a disorder that causes unusual shifts in mood, energy, activity levels, and the ability to carry out day-to-day tasks.

There are three defined sub-categories of bipolar disorder; all of them involve clear changes in mood, energy, and activity levels. These moods range from periods of extremely "up," elated, and energized behaviour (known as manic episodes) to very sad, "down," or hopeless periods (known as depressive episodes). Less severe manic periods are known as hypomanic episodes.

Bipolar I Disorder— defined by manic episodes that last at least 7 days, or by manic symptoms that are so severe that the person needs immediate hospital care. Usually, depressive episodes occur as well, typically lasting at least 2 weeks. Episodes of depression with mixed features (having depression and manic symptoms at the same time) are also possible.

Bipolar II Disorder— defined by a pattern of depressive episodes and hypomanic episodes, but not the full-blown manic episodes described above.

Cyclothymic Disorder (also called cyclothymia)— defined by numerous periods of hypomanic symptoms as well numerous periods of depressive symptoms lasting for at least 2 years (1 year in children and adolescents). However, the symptoms do not meet the diagnostic requirements for a hypomanic episode and a depressive episode.

Psychotic depression, also known as depressive psychosis, is defined as a major depressive episode that is accompanied by psychotic symptoms including hallucinations and delusions.

Postpartum depression as referred to herein refers to a diagnosis that meets the criteria for major depression when occurring in a mother within the first year from giving birth.

Premenstrual dysphoric disorder as referred to herein, is present in a patient who meets the following criteria A-C.

Criterion A is that in most menstrual cycles during the past year, at least 5 of the following 11 symptoms (including at least 1 of the 4 listed) must be present in the final week before the onset of menses, start to improve within a few days after the onset of menses, and become minimal or absent in the week postmenses.

1. Marked lability (e.g., mood swings)

2. Marked irritability or anger

3. Markedly depressed mood

4. Marked anxiety and tension

5. Decreased interest in usual activities

6. Difficulty in concentration

Lethargy and marked lack of energ

8. Marked change in appetite (e.g., overeating or specific food cravings)

9. Hypersomnia or insomnia 10. Feeling overwhelmed or out of control

11. Physical symptoms (e.g., breast tenderness or swelling, joint or muscle pain, a

sensation of 'bloating' and weight gain)

Criterion B one (or more) of the following symptoms must be present:

1. Marked affective lability (e.g., mood swings; feeling suddenly sad or tearful, or

increased sensitivity to rejection).

2. Marked irritability or anger or increased interpersonal conflicts.

3. Marked depressed mood, feelings of hopelessness, or self-deprecating thoughts.

4. Marked anxiety, tension, and/or feelings of being keyed up or on edge.

Criterion C one (or more) of the following symptoms must be additionally be present, to reach a total of five symptoms when combined with symptoms from Criterion B above.

1. Decreased interest in usual activities (e.g., work, school, friends, hobbies).

2. Subjective difficulty in concentration.

3. Lethargy, easy fatigability, or marked lack of energy.

4. Marked change in appetite; overeating; or specific food cravings.

5. Hypersomnia or insomnia.

6. A sense of being overwhelmed or out of control.

7. Physical symptoms such as breast tenderness or swelling, joint or muscle pain, a sensation of "bloating," or weight gain.

The symptoms in Criteria A-C must have been met for most menstrual cycles that occurred in the preceding year.

Suicidality is defined as two or more incidents of thoughts of death or suicide over a two week period, or a suicide attempt.

Anhedonia is defined as inability to feel pleasure in normally pleasurable activities.

Atypical depression is a subtype of major depression or dysthymic disorder that involves several specific symptoms, including increased appetite or weight gain, sleepiness or excessive sleep, marked fatigue or weakness, moods that are strongly reactive to

environmental circumstances, and feeling extremely sensitive to rejection.

As used herein, the term 'anxiety disorder' is defined as a category of mental disorders characterized by feelings of anxiety and fear including one of the following experiential aspects: mental apprehension, physical tension, physical symptoms and dissociative anxiety. Specific anxiety disorders include generalized anxiety disorder, phobias, panic disorder, agoraphobia, social anxiety disorder, post-traumatic stress disorder, separation anxiety, and obsessive-compulsive disorder.

Generalized anxiety disorder (GAD) as used herein means a chronic disorder characterized by long-lasting anxiety that is not focused on any one object or situation. Those suffering from generalized anxiety disorder experience non-specific persistent fear and worry, and become overly concerned with everyday matters. GAD is characterized by chronic excessive worry accompanied by three or more of the following symptoms: restlessness, fatigue, concentration problems, irritability, muscle tension, and sleep disturbance.

A phobia is defined as a persistent fear of an object or situation the affected person will go to great lengths to avoid, typically disproportional to the actual danger posed. If the feared object or situation cannot be avoided entirely, the affected person will endure it with marked distress and significant interference in social or occupational activities.

A patient suffering a from a panic disorder is defined as one who experiences one or more brief attack (also referred to as a panic attack) of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, and/or difficulty breathing. A panic attack is defined as a fear or discomfort that abruptly arises and peaks in less than ten minutes.

Agoraphobia is the specific anxiety about being in a place or situation where escape is difficult or embarrassing or where help may be unavailable. Agoraphobia is strongly linked with panic disorder and is often precipitated by the fear of having a panic attack.

Social anxiety disorder is defined as an intense fear and avoidance of negative public scrutiny, public embarrassment, humiliation, or social interaction. Social anxiety often manifests specific physical symptoms, including blushing, sweating, and difficulty speaking. Post-traumatic stress disorder (PTSD) is an anxiety disorder that results from a traumatic experience. Post-traumatic stress can result from an extreme situation, such as combat, natural disaster, rape, hostage situations, child abuse, bullying, or even a serious accident. Common symptoms include hypervigilance, flashbacks, avoidant behaviors, anxiety, anger and depression.

Separation anxiety disorder is the feeling of excessive and inappropriate levels of anxiety over being separated from a person or place. Separation anxiety is a normal part of development in babies or children, and it is only when this feeling is excessive or inappropriate that it can be considered a disorder.

Obsessive-compulsive disorder (OCD) is a condition where the sufferer has obsessions (distressing, persistent, and intrusive thoughts or images) and/or compulsions (urges to repeatedly perform specific acts or rituals), that are not caused by drugs or physical order, and which cause distress or social dysfunction. The compulsive rituals are personal rules followed to relieve the anxiety. OCD affects roughly 1-2% of adults (somewhat more women than men), and under 3% of children and adolescents.

As used herein the term 'blister pack' means a type of pre-formed packaging having a cavity or pocket which can contain a dosage form, and where the dosage form can readily break through a covering membrane. Often the covering membrane is made of metal foil, e.g. aluminium foil. DESCRIPTION OF THE INVENTION

The present invention provides conformationally stabilized analogues of 6-hydroxyketamine and 6-hydroxynorketamine with applications in the treatment of depression disorders and anxiety disorders. Compounds of the present invention have a number of advantages including efficient and scalable stereospecific synthesizability, high stability, and good oral bioavailability.

A first aspect of the present invention provides a compound of Formula I

I

wherein R¹ is H or C1-C4 alkyl; R² is H or C1-C4 alkyl; R³ is H or C1-C4 alkyl; R⁴ is H or Ci- C₄ alkyl; R⁵ is H or C1-C4 alkyl; R⁵ is H or C1-C4 alkyl; and R⁶ represents 0, 1, 2, 3, 4 or 5 haloatoms each independently selected from F, CI, Br, I. Preferably, when R² is H at least one of R³, R⁴, and R⁵ is not H.

In preferred embodiments R¹ is H or Me. In preferred embodiments R³ is H or Me. In preferred embodiments R⁴ is H or Me. In preferred embodiments R³ and R⁴ are both Me. In preferred embodiments R⁵ is selected from H, Me, Et, i-Pr or t-Bu. In preferred embodiments either R⁵ is i-Pr or t-Bu or one or both of R³ and R⁴ are Me.

In preferred embodiments R² is H and at least one of R³, R⁴, and R⁵ is not H, so that one of two possible chair confirmations is favoured.

In preferred embodiments R² is selected from Me, Et, i-Pr or t-Bu.

In preferred embodiments R⁶ represents one haloatom selected from F, CI, Br, and I, which is ortho to the C-C bond linking the aryl group to the cyclohexanone. In preferred embodiments R⁶ represents two haloatoms selected from F, CI, Br, and I, preferably one or both of which are ortho to the C-C bond linking the aryl group to the cyclohexanone. In preferred embodiments R⁶ represents one or two haloatoms which are ortho to the C-C bond linking the aryl group to the cyclohexanone. In preferred embodiments R⁶ represents one haloatom selected from F, CI, Br, and I. In preferred embodiments R⁶ represents two separate haloatoms independently selected from F, CI, Br, and I, preferably one or both of which are ortho to the C-C bond linking the aryl group to the cyclohexanone. In preferred embodiments R⁶ represents three separate haloatoms independently selected from F, CI, Br, and I, preferably one or more of which are ortho to the C-C bond linking the aryl group to the cyclohexanone. In preferred embodiments R⁶ represents three separate haloatoms independently selected from F, CI, Br, and I, wherein two haloatoms are ortho and one is para to the C-C bond linking the aryl group to the cyclohexanone. In preferred embodiments R⁶ represents the same haloatom selected from F, CI, Br, and I. In preferred embodiments R⁶ represents CI. In preferred embodiments R⁶ represents one CI. In preferred embodiments R⁶ represents two separate CI, preferably one or more of which are ortho to the C-C bond linking the aryl group to the cyclohexanone. In preferred embodiments R⁶ represents three separate CI, preferably one or more of which are ortho to the C-C bond linking the aryl group to the cyclohexanone. In preferred embodiments at least one haloatom represented by R⁶ is CI. In preferred embodiments, all haloatoms represented by R⁶ are CI.

A second aspect of the present invention provides a compound having the structure of Formula II or Formula III or the opposite enantiomer thereof, or a pharmaceutically acceptable salt thereof;

Formula III

wherein:

(i) R¹ is H or C1-C4 alkyl, R² is H or C1-C4 alkyl, R³ is H or C1-C4 alkyl, R⁴ is H or C1-C4 alkyl, R⁵ is H or C1-C4 alkyl, R⁶ is H or C1-C4 alkyl, and R⁷ represents 0, 1, 2, 3, 4 or 5 haloatoms each independently selected from F, CI, Br, I, provided that when R² is H one or both of R3 and R4 is C1-C4 alkyl, or R5 is C1-C4 alkyl; or

(ii) R¹ is H or C1-C4 alkyl, R² is -PO3H2 or -SO3H, R³ is H or C1-C4 alkyl, R⁴ is H or C1-C4 alkyl, R⁵ is H or C1-C4 alkyl, and R⁶ represents 0, 1, 2, 3, 4 or 5 haloatoms each

independently selected from F, CI, Br, I; or

(iii) R¹ and R² are combined to form -(CO)-, -(SO2)-, or -(PO2H)-, the compound has the confirmation of Formula II, R³ is H or C1-C4 alkyl, R⁴ is H or C1-C4 alkyl, R⁵ is H or C1-C4 alkyl, and R⁶ represents 0, 1, 2, 3, 4 or 5 haloatoms each independently selected from F, CI, Br, I.

Preferably, the compounds of the present invention have the stereochemistry of Formula II or III.

In a preferred embodiment, the compounds of the invention, or pharmaceutically acceptable salts thereof have a structure of Formula IV or V or the opposite enantiomer thereof, or a pharmaceutically acceptable salt thereof

Formula IV Formula V

wherein:

(i) R¹ is H or C1-C4 alkyl, R² is H or C1-C4 alkyl, R³ is H or C1-C4 alkyl, R⁴ is H or C1-C4 alkyl, R⁵ is H or C1-C4 alkyl, and R⁶ is selected from F, CI, Br, and I, provided that one or both of R3 and R4 is C1-C4 alkyl, or R5 is C1-C4 alkyl; or

(ii) R¹ is H or C1-C4 alkyl, R² is -PO3H2 or -SO3H, R³ is H or C1-C4 alkyl, R⁴ is H or C1-C4 alkyl, R⁵ is H or C1-C4 alkyl, and R⁶ is selected from F, CI, Br, and I; or

(iii) R¹ and R² are combined to form -(CO)-, -(SO2)-, or -(PO2H)-, the compound has conformation of Formula IV, R³ is H or C1-C4 alkyl, R⁴ is H or C1-C4 alkyl, R⁵ is H or C1-C4 alkyl, and R⁶ is selected from F, CI, Br, and I.

Preferred embodiments of the invention are compounds of Formula II, III, IV or V or the enantiomer thereof, or a pharmaceutically acceptable salts thereof, wherein

(i) R¹ is H, R² is H or C1-C4 alkyl, R³ is H or C1-C4 alkyl, R⁴ is H or C1-C4 alkyl, and R⁵ is H or C1-C4 alkyl, provided that either (a) one or both of R³ and R⁴ is C1-C4 alkyl, or (b) R⁵ is C1-C4 alkyl; or

(ii) R¹ is H, R² is -PO3H2 or -SO3H, R³ is H or C1-C4 alkyl, R⁴ is H or C1-C4 alkyl, and R⁵ is H or C1-C4 alkyl; or

(iii) R¹ and R² are combined to form -(CO)-, -(S0₂)-, or -(P0₂H)-, R³ is H or C1-C4 alkyl, R⁴ is H or C1-C4 alkyl, and R⁵ is H or C1-C4 alkyl.

Preferred embodiments of the invention are compounds of Formula II, III, IV or V or the opposite enantiomer thereof, or pharmaceutically acceptable salts thereof, wherein

(i) Ri and R2 are H, and either (a) R3 and R4 are each Me and R5 is H, or (b) R3 and R4 are each H and R5 is t-butyl; or

(ii) Ri is H, R2 is -PO3H2 or -SO3H, and R3, R4 and R5 are each H; or

(iii) Ri and R2 are combined to form -(CO)-, -(SO2)-, or -(PO2H)-, and R3, R4 and R5 are each H.

Particularly preferred embodiments of the invention are compounds of Formula II, III, IV or V or the opposite enantiomer thereof, or pharmaceutically acceptable salts thereof, wherein R² is -PO3H2. Particularly preferred embodiments of the invention are compounds of Formula II, III, IV or V or the opposite enantiomer thereof, or pharmaceutically acceptable salts thereof, wherein R¹ is H.

Preferred embodiments of the invention are compounds of Formula II, III, IV or V or the opposite enantiomer thereof, or pharmaceutically acceptable salts thereof, wherein R¹ is Me.

Preferred embodiments of the invention are compounds of Formula II, III, IV or V or the opposite enantiomer thereof, or pharmaceutically acceptable salts thereof, wherein R¹ and R² are combined to form -(CO)-.

Preferred embodiments of the invention are compounds of Formula II, III, IV or V or the opposite enantiomer thereof, or pharmaceutically acceptable salts thereof, wherein R⁶ represents 0, 1, 2, or 3 haloatoms independently selected from F, CI, Br, and I. Preferably R⁶ represents one haloatom selected from F, CI, Br, and I, which is ortho to the C-C bond linking the aryl group to the cyclohexanone. Preferably R⁶ represents two haloatoms selected from F, CI, Br, and I, preferably one or both of which are ortho to the C-C bond linking the aryl group to the cyclohexanone. Preferably one or two haloatoms are ortho to the C-C bond linking the aryl group to the cyclohexanone. Preferably, R⁶ represents one haloatom selected from F, CI, Br, and I. Preferably, R⁶ represents two separate haloatoms independently selected from F, CI, Br, and I, preferably one or both of which are ortho to the C-C bond linking the aryl group to the cyclohexanone. Preferably, R⁶ represents three separate haloatoms independently selected from F, CI, Br, and I, preferably one or more of which are ortho to the C-C bond linking the aryl group to the cyclohexanone. Preferably, R⁶ represents three separate haloatoms independently selected from F, CI, Br, and I, wherein two haloatoms are ortho and one is para to the C-C bond linking the aryl group to the cyclohexanone.

Preferably R⁶ represents the same haloatom selected from F, CI, Br, and I. Preferably, R⁶ represents CI. Preferably, R⁶ represents one CI. Preferably, R⁶ represents two separate CI, preferably one or more of which are ortho to the C-C bond linking the aryl group to the cyclohexanone. Preferably, R⁶ represents three separate CI, preferably one or more of which are ortho to the C-C bond linking the aryl group to the cyclohexanone. Preferably at least one haloatom represented by R⁶ is CI. Preferably, all haloatoms represented by R⁶ are CI.

Preferred embodiments of the invention are compounds of Formula III, or pharmaceutically acceptable salts thereof, wherein R⁶ is CI.

Preferred compounds of the present invention have R³ and/or R⁴ on the same face as the aryl or where R⁵ is on the opposite face to the aryl. Preferred compounds of Formula I are selected from Compounds 1-24:

In a third aspect of the present invention is a compounds of Formula I, II, III, IV or V or the opposite enantiomer thereof, or a pharmaceutically acceptable salts thereof, for use in treating a patient suffering from a depressive disorder or an anxiety disorders.

In preferred embodiments the depressive disorder is selected from major depressive disorder (MDD), persistent depressive disorder, bipolar disorder, psychotic depression, post-partum depression, premenstrual dysphoric disorder (PMDD), atypical depression, suicidality, anhedonia.

In preferred embodiments the anxiety disorder is selected from generalised anxiety disorder (GAD), phobia, posttraumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), panic disorders, agoraphobia, Tourette's syndrome, social anxiety disorder and separation anxiety.

In embodiments of the invention, the compounds of the invention, or pharmaceutically acceptable salts thereof are for use as a first-line therapy.

In preferred embodiments the anxiety disorder is generalized anxiety disorder (GAD). In preferred embodiments the anxiety disorder is obsessive-compulsive disorder (OCD). In preferred embodiments the depressive disorder is major depressive disorder (MDD).

In preferred embodiments the depressive disorder is suicidality.

In embodiments of the invention, the compounds of the invention, or pharmaceutically acceptable salts thereof, are for use in combination with a serotonin modulator.

In preferred embodiments the serotonin modulator is a selective serotonin reuptake inhibitor (SSRI).

The compound or salt of the present invention and the serotonin modulator may be administered simultaneously, sequentially or separately.

In preferred embodiments of the present invention, the compound or salt of the present invention are for use in treating a patient wherein said patient has not previously been treated with an anti-anxiety agent.

In preferred aspects of the present invention, the compound or salt of the present invention are for use in treating a patient wherein said patient has not previously been treated with an antidepressant agent.

In preferred embodiments of the present invention, the compound or salt of the present invention are for use in treating a patient who has failed to achieve adequate control of the symptoms of said depressive disorder or said anxiety disorder using psychotherapy alone.

In preferred embodiments the compound of the present invention is formulated as a solid oral dosage form. The solid oral dosage form of the present invention is preferably selected from a pill, capsule, caplet, tablet, powder, buccal tablet, buccal film or sublingual film. Preferably the solid oral dosage form is a tablet or a capsule. Most preferably the solid oral dosage form is a tablet. In certain embodiments of the invention, the solid oral dosage form is film coated, for example a film coated tablet.

In embodiments of the invention, the dosage form comprises from about O. lmg to about lg of a compound of the invention or a pharmaceutically acceptable salt thereof.

Preferably the dosage form or solid oral dosage form of the present invention comprises from about lmg to about 200mg of a compound of the invention or a pharmaceutically acceptable salt thereof.

More preferably the dosage form or solid oral dosage form of the present invention comprises from about 5 mg to about 50 mg of a compound of the invention or a pharmaceutically acceptable salt thereof.

In particularly preferred embodiments of the invention, the dosage form is a solid oral dosage form contained of the compound of the invention is selected from 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg and 50 mg.

In embodiments of the invention, the compounds of the invention, or pharmaceutically acceptable salts thereof, are for use in combination with a serotonin modulator, wherein the serotonin modulator is selected from Citalopram, Escitalopram, Paroxetine, Fluoxetine, Fluvoxamine, Sertraline, Desvenlafaxine, Duloxetine, Levomilnacipran, Milnacipran, Tofenacin, Venlafaxine, Vilazodone, Vortioxetine, Etopendone, Nefazodone, and Trazodone, or a pharmaceutically acceptable salt thereof.

Preferably the serotonin modulator is selected from Citalopram, Escitalopram, Paroxetine, Sertraline, Duloxetine, and Venlafaxine, or a pharmaceutically acceptable salt thereof.

In particularly preferred embodiments the serotonin modulator is selected from Citalopram and Escitalopram, more preferably the serotonin modulator is Escitalopram.

The present invention also provides a kit comprising a package and one or more unit dose(s), wherein each unit dose comprises a dosage form comprising a compound of the present invention or a pharmaceutically acceptable salt thereof.

In preferred embodiments of the invention, the kit comprises a package and one or more unit dose(s) wherein each unit dose is a solid oral dosage form.

Preferably the kit of the present invention comprises 28 unit doses.

Preferably the kit of the present invention comprises unit doses packaged in one or more blister packs. Preferably the blister pack is a foil blister pack. Preferably the blister pack displays identifier(s) to indicate the date and/or time at which each unit dose is to be administered.

SYNTHESIS

Compounds according to the present invention are synthesised according to the process described in Scheme 1 or 2.

I

Scheme 1

where L represents a suitable leaving group.

EXAMPLES

Compound 3 is synthesised following the method described in Scheme 3 :

Scheme 2

Compound 102

Compound 101 as a solution in ethyl acetate is treated with copper (II) bromide (2.2 Eq.) and the suspension heated to reflux over 4 hours. Gases are scrubbed with a water scrubber. The reaction mixture is allowed to cool overnight. The reaction mixture is filtered through a pad of silica and washed twice with ethyl acetate. The solvent is removed to leave Compound 102. Compound 103

Compound 102 is stirred whilst liquid ammonia (large excess) is added over 5 minutes. The mixture is stirred over 4 h and the ammonia is allowed to evaporate slowly. The residue (a solid mass) is dissolved in THF and stirred at 40°C for 30 min. The suspension is allowed to cool to room temperature and filtered to remove the inorganics. The solid is washed with THF and the filtrates are evaporated to leave the product 103.

Compound 104

Compound 103 is dissolved in isobutanol and heated to reflux for 18 hours. The solvent is removed to leave Compound 104.

Compound 105

Compound 104 is suspended in dry THF with stirring under an argon atmosphere; to the stirring solution NEt₃ is added as a single portion over 30 seconds. Di-tert-butyl-di carbonate is added to the reaction vessel as a single portion under an argon stream and following the complete addition the reaction is heated to 70 °C for 18 h. The reaction is then cooled to room temperature and diluted with EtOAc then washed with saturated NH₄C1 then the separated organic phase washed with brine, dried over Na₂S04, filtered and then concentrated in vacuo to afford crude compound. Crude material is purified via flash column chromatography to afford Compound 105.

Compound 106

Diisopropylamine is dissolved in dry THF with stirring under an argon atmosphere then the mixture is cooled to -78 °C. Freshly titrated n-BuLi is added dropwise over 2 minutes and the reaction mixture is stirred for 15 minutes; after which a solution of Compound 105 in dry THF is added dropwise over 2 minutes and the reaction stirred for 25 minutes.

Chlorotrimethylsilane is added to the reaction dropwise and the reaction stirred for 15 minutes at -78 °C then warmed to 0 °C and stirred for 1 h. After this time the reaction is diluted with heptane, washed with NaHC0₃ and the organic phase is separated and dried over Na₂S0₄, filtered and then concentrated in vacuo to afford crude Compound 106. The crude product is purified via column chromatography to afford Compound 106 as a clear colourless oil.

Compound 107

Compound 106 is dissolved in dichloromethane and cooled to -15 °C under a nitrogen atmosphere. 3-Chloroperbenzoic acid is then added as a solid. The reaction is stirred for one hour at -15 °C, then the temperature is raised to room temperature and additional

dichloromethane is added. The reaction is stirred a further 0.5 hours. The reaction is then quenched by being poured into a 50/50 mixture of saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate. The reaction is extracted into dichloromethane and the solvent removed by rotary evaporation. Then THF is added to the crude material. The reaction is cooled to -5 °C, and 1.0 M tetrabutylbutyl ammonium fluoride in THF is added. The reaction is stirred for 2 minutes, before being quenched by addition to saturated aqueous sodium bicarbonate. Extraction into ethyl acetate, and removal of the solvent by rotary evaporation gives the crude final product Compound 107. Purification by silica gel chromatography gives the purified final product as solid Compound 107. Compound 3

Compound 107 is transferred into a round bottom flask under an argon atmosphere with a stirrer bar and a large excess of HC1 is added with stirring, and the reaction stirred under an argon atmosphere for 18 hours. After this time the reaction is filtered to collect the formed precipitate, which is then washed with pentane and dried under an argon stream to afford the hydrochloride salt of Compound 3 as a white crystalline solid.

Claims

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof;

I

wherein R¹ is H or C1-C4 alkyl; R² is H or C1-C4 alkyl; R³ is H or C1-C4 alkyl; R⁴ is H or Ci- C₄ alkyl; R⁵ is H or Ci-C alkyl; R⁵ is H or Ci-C alkyl; and R⁶ represents 0, 1, 2, 3, 4 or 5 haloatoms each independently selected from F, CI, Br, I; with the proviso that when R² is H at least one of R³, R⁴, and R⁵ is not H.

2. The compound of claim 1 wherein

a. R¹ is H or Me; and/or

b. R³ is H or Me; and/or

c. R⁴ is H or Me; and/or

d. R³ and R⁴ are both Me; and/or

e. R⁵ is selected from H, Me, Et, i-Pr or t-Bu.

3. The compound of claim 1 or 2 wherein at least one of R³, R⁴, and R⁵ is not H, such that one of two possible chair confirmations is favoured.

4. The compound of claim 1 to 3 wherein R² is selected from Me, Et, i-Pr or t-Bu.

5. The compound of any one of claims 1 to 4 wherein

a. R⁶ represents one haloatom selected from F, CI, Br, and I, which is ortho to the C-C bond linking the aryl group to the cyclohexanone; or b. R⁶ represents two haloatoms selected from F, CI, Br, and I, or

c. R⁶ represents three separate haloatoms independently selected from F, CI, Br, and I wherein one or more of which are ortho to the C-C bond linking the aryl group to the cyclohexanone; or

d. R⁶ represents three separate haloatoms independently selected from F, CI, Br, and I, wherein two haloatoms are ortho and one is para to the C-C bond linking the aryl group to the cyclohexanone.

6. The compound of any one of claims 1 to 5 wherein R⁶ represents the same haloatom selected from F, CI, Br, and I.

7. The compound of claim 6 wherein R⁶ represents CI. A compound of Formula II or Formula III or the opposite enantiomer thereof, or a pharmaceutically acceptable salt thereof;

Formula II Formula III

wherein:

independently selected from F, CI, Br, I; or

(iii) R¹ and R² are combined to form -(CO)-, -(SO2)-, or -(PO2H)-, the compound has conformation of Formula II, R³ is H or C1-C4 alkyl, R⁴ is H or C1-C4 alkyl, R⁵ is H or C1-C4 alkyl, and R⁶ represents 0, 1, 2, 3, 4 or 5 haloatoms each independently selected from F, CI, Br, I.

9. The compound of claim 8 having a structure of Formula IV or V or the opposite enantiomer thereof, or a pharmaceutically acceptable salt thereof

Formula IV Formula V

wherein: (i) R¹ is H or C1-C4 alkyl, R² is H or C1-C4 alkyl, R³ is H or C1-C4 alkyl, R⁴ is H or C1-C4 alkyl, R⁵ is H or C1-C4 alkyl, and R⁶ is selected from F, CI, Br, and I, provided that one or both of R3 and R4 is C1-C4 alkyl, or R5 is C1-C4 alkyl; or

(iii) R¹ and R² are combined to form -(CO)-, -(SO2)-, or -(PO2H)-, the compound has conformation of Formula IV, R³ is H or C1-C4 alkyl, R⁴ is H or C1-C4 alkyl, R⁵ is H or C1-C4 alkyl, and R⁶ is selected from F, CI, Br, and I. 10. The compound of claim 8 or 9 wherein

(iii) R¹ and R² are combined to form -(CO)-, -(SO2)-, or -(PO2H)-, the compound has conformation of Formula II or IV, R³ is H or C1-C4 alkyl, R⁴ is H or C1-C4 alkyl, and R⁵ is H or C1-C4 alkyl.

11. The compound of any one of claims 8 to 10 wherein

(ii) Ri is H, R2 is -PO3H2 or -SO3H, and R3, R4 and R5 are each H; or

(iii) Ri and R2 are combined to form -(CO)-, -(SO2)-, or -(PO2H)-, the compound has conformation of Formula II or IV, and R3, R4 and R5 are each H.

12. The compound of any one of claims 8 to 11 wherein R¹ and R² are combined to form -(CO)-.

13. The com ound of claim 1 selected from Compounds 1-24:

14. The compound of any one of claims 1 to 13 for use in treating a patient suffering from a depressive disorder or an anxiety disorders.

15. The compound of any one of claims 1 to 13 for use in treating a patient suffering from a disorder selected from major depressive disorder (MDD), persistent depressive disorder, bipolar disorder, psychotic depression, post-partum depression, premenstrual dysphoric disorder (PMDD), atypical depression, suicidality, anhedonia, generalised anxiety disorder (GAD), phobia, posttraumatic stress disorder (PTSD), obsessive- compulsive disorder (OCD), panic disorders, agoraphobia, Tourette's syndrome, social anxiety disorder and separation anxiety.

16. The compound of any one of claims 1 to 15 for use as a first-line therapy.

17. The compound of any one of claims 1 to 16 for use in combination with a serotonin modulator.

18. The compound claim 17 wherein the serotonin modulator is a selective serotonin reuptake inhibitor (SSRI).

19. The compound of claim 17 wherein the serotonin modulator is selected from

Citalopram, Escitalopram, Paroxetine, Sertraline, Duloxetine, and Venlafaxine, or a pharmaceutically acceptable salt thereof.

20. The compound of any one of claims 1 to 19 formulated as a solid oral dosage form selected from a pill, capsule, caplet, tablet, powder, buccal tablet, buccal film or sublingual film.

21. A kit comprising a package and one or more unit dose(s), wherein each unit dose comprises a solid oral dosage form comprising a compound of any one of claims 1 to 20.

22. The kit of claim 21 comprising 28 unit doses.